Annulated heterocyclic bioisosteres of norarecoline. Synthesis and molecular pharmacology at five recombinant human muscarinic acetylcholine receptors.

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Brauner-Osborne H, Ebert B, Brann MR, Falch E, Krogsgaard-Larsen P

Annulated heterocyclic bioisosteres of norarecoline. Synthesis and molecular pharmacology at five recombinant human muscarinic acetylcholine receptors.

J Med Chem. 1995 Jun 9;38(12):2188-95.

PubMed ID
7783150 [ View in PubMed
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Abstract

A series of O-alkylated analogs of 5,6,7,8-tetrahydro-4H-isoxazolo[4,5-c]azepin-3-ol (THAO) were synthesized and characterized as ligands for muscarinic acetylcholine receptors (mAChRs). O-Methyl-THAO (4a), O-ethyl-THAO (4b), O-isopropyl-THAO (4c), and O-propargyl-THAO (4d) were shown to be potent inhibitors of the binding of tritiated quinuclidinyl benzilate (QNB), pirenzepine (PZ), and oxotremorine-M (Oxo-M) to tissue membrane preparations. In the [3H]-Oxo-M binding assay, receptor affinities in the low nanomolar range were measured for 4a (IC50 = 0.010 microM), 4b (IC50 = 0.003 microM), 4c (IC50 = 0.011 microM), and 4d (IC50 = 0.0008 microM). Pharmacological effects (EC50 or Ki values) and intrinsic activities (per cent of maximal carbachol responses) were determined using five recombinant human mAChRs (m1-m5) and the functional assay, receptor selection and amplification technology (R-SAT). Compound 4c antagonized carbachol-induced responses at m1, m3, and m5. With the exception of 4b, which was an antagonist at m5, 4a,b,d showed partial agonism at m1-m5 with very similar subtype selectivity (m2 > m4 > m1 > or = m3 > m5). Agonist index values for 4a-d, which were calculated from [3H]QNB (brain) and [3H]Oxo-M (brain) binding data, were shown to be predictive of pharmacologically determined intrinsic activities at m1-m5, the same rank order of intrinsic activity being observed at all five mAChRs (4a > 4d > 4b > 4c). It is concluded that within this class of high-affinity mAChR (m1-m5) ligands, containing secondary amino groups, minor changes of the bioisosteric ester alkyl groups have marked effects on potency and, in particular, intrinsic activity.

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
ArecolineMuscarinic acetylcholine receptor M1EC 50 (nM)3200N/AN/ADetails
ArecolineMuscarinic acetylcholine receptor M3EC 50 (nM)340N/AN/ADetails
CarbamoylcholineMuscarinic acetylcholine receptor M1EC 50 (nM)4600N/AN/ADetails
CarbamoylcholineMuscarinic acetylcholine receptor M2EC 50 (nM)74N/AN/ADetails
CarbamoylcholineMuscarinic acetylcholine receptor M3EC 50 (nM)1800N/AN/ADetails
CarbamoylcholineMuscarinic acetylcholine receptor M4EC 50 (nM)75N/AN/ADetails